Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management

Stroes ES, Thompson PD, Corsini A, et al.
Eur Heart J published 18 February 2015, 10.1093/eurheartj/ehv043

Although statin therapy for prevention and treatment of cardiovascular disease (CVD) is effective and generally safe and well-tolerated, myositis may be seen a rare side-effect. This is defined as muscle symptoms in association with a substantially elevated serum creatine kinase (CK) concentration. Elevations > 10 times the upper limit of normal (ULN) of this enzyme that is released from damaged muscle cells are seen in 1 per 1000 to 1 per 10.000 people per year, depending on the statin used, the dose and the risk profile.
Although in randomised, controlled trials (RCTs), adverse event rates, including muscle symptoms,  were found to be similar in statin and placebo groups, patient registries and clinical experience indicate that 7-29% of patients complain of statin-associated muscle symptoms (SAMS). SAMS likely contribute to the high discontinuation rate of statin therapy.
Several aspects may play a role in the observed discrepancy in reported rates of muscle symptoms between observational studies and RCTs. The only randomised, double-blind, placebo-controlled Effects of Statins on Muscle Performance (STOMP) study reported myalgia in 9.4% of statin-treated and 4.6% of control subjects. Muscle strength and exercise performance were not different between treatment groups in STOMP. Thus, the incidence of SAMS appears to be lower than reported in observational studies, but given the widespread use of statins, even a small increase in myalgia rates would still mean that a substantial number of patients is affected.
Some studies suggest that statin-attributed complaints may in fact have other causes, or are not generalizable to other statins. This report is an overview of the science underlying the pathophysiology of statin-induced myopathy and clinical guidance on the diagnosis and management of SAMS, composed by a European Atherosclerosis Society (EAS) Consensus Panel.
 Because symptoms are variable and subjective and since no ‘gold standard’ diagnostic test exists, it is hard to make a definite SAMS diagnosis. A symptom scoring system has been proposed by the National Lipid Association based on the STOMP trial and the PRIMO survey. The Consensus Panel proposes that the muscle symptoms, elevation in CK levels, and their temporal association with statin initiation, discontinuation and re-challenge be taken into account when assessing the probability of SAMS.  
The majority of SAMS cases are not accompanied by marked CK elevations. The risk of having CK elevation depends on the dose of statin, as well as on factors associated with increased statin blood concentrations (genetic factors, ethnicity, interacting drugs, patient characteristics, etc.). Since with a standard dose of statin, the risk of CK elevations > 10x ULN is about 1 in 10.000 per year, it is not recommended to routinely monitor CK levels.

Management of statin-associated muscle symptoms

If a patient complains of muscle symptoms, the clinician should evaluate risk factors that may predispose to SAMS (female gender, ethnicity, multisystem disease, and small body frame), exclude secondary causes (especially hypothyroidism) and review the indication for statin use. Also, it should be noted that other commonly prescribed drugs may also cause muscle-related side-effects and drug-drug interactions that affect statin levels may increase the risk of SAMS.

* Patients with muscle symptoms with serum CK <4x ULN

Most patients with muscle complaints have normal or mild/moderately elevated CK levels (<4x ULN). If they are at low CV risk, their need for a statin should be reconsidered, and the benefits of lifestyle changes should be weighed against the risk of continuing statin therapy.
For those at high risk of CVD, the benefits of ongoing statin therapy and the burden of muscle symptoms need to be balanced. Discontinuation of statin therapy and re-challenges after a washout period can help to determine causality, or an alternative statin may be tried, or a different dosing scheme, or another class of lipid-lowering medication.

* Patients with muscle symptoms and elevated serum CK (>4x ULN)

If a patient is at low CVD risk, the need for statin should be reassessed, and a lower dose of an alternative statin may be tried, while monitoring CK.
In patients at high CVD risk, the statin should be continued while monitoring CK levels. If CK exceeds 10x ULN, the specific statin regimen used should be stopped and not restarted. If CK levels drop upon stopping the statin, restarting at a lower dose may be tried, with CK monitoring. If CK elevation persists, referral to a neuromuscular specialist may be considered to assess possible underlying myopathy.
In patients with CK >10x ULN in the absence of a known secondary cause, statin therapy should be stopped because of the risk of rhabdomyolysis. This is a severe form of muscle damage, which should be considered in case of severe muscle pain, general weakness and signs of myoglobinaemia or myoglobinuria. It may be associated with renal damage. If CK levels return to normal after stopping statin therapy, a lower dose of an alternative statin may be tried, with careful monitoring of symptoms and CK level.

Current therapy for patients with SAMS

* Statin-based therapies

Re-challenging with lower doses of the same statin, or switching to another statin should be considered if symptoms and CK levels resolve after discontinuation. Doses can be up-titrated to achieve better LDL-c lowering. If this is not tolerated, non-daily regimens can be considered; alternate day and twice-weekly strategies have been shown to reduce LDL-c by 12-38% and are tolerated by a majority of previously intolerant patients. Lower doses of a high-intensity statin with a long half-life (atorvastatin, rosuvastatin, pitavastatin) generally appear more appropriate.

* Non-statin-based lipid-lowering therapy

If LDL-c target is not met with maximally tolerated statin therapy, other LDL-lowering medication should be considered in patients with high CVD risk. Ezetimibe is well tolerated and lowers LDL-c by 15-20%. In case of SAMS, in combination with fluvastatin XL it reduced LDL-c by 46%, while being well tolerated. Bile acid sequestrants may also be given, possibly in combination with ezetimibe. Fenofibrate can be used to lower LDL-c in patients who do not have concomitant hypertriglyceridaemia. It is easy to use and safe, but no additional CVD benefit has been demonstrated, and serum creatinine was reversibly elevated during treatment. Niacin also lowers LDL-c levels, but due to an excess of adverse effects and lack of CVD benefit when added to background statin therapy in large randomised trials, it is no longer available for prescription in Europe.

* Nutraceuticals

Consumption of a low saturated fat diet, avoidance of trans fats, consumption of viscous fibre and foods with added plant sterols or stanols can also lower LDL-c levels. The Portfolia diet, incorporating plant sterols, soya protein, viscous fibres and nuts, can even lower LDL-c levels by 20-25%. The Panel believes that these strategies may be employed in patients with SAMS either alone or in combination with drug therapy.

* Complementary therapies

Use of ubiquinone (coenzyme Q10) and vitamin D supplementation have been proposed to improve statin tolerability. Since the effectiveness of these complementary therapies is controversial, the Panel does not recommend supplementation with these products.
Red yeast rice is a fermented product that has been shown to reduce LDL-c levels in short-term RCTs. Its effect on the long term is, however, unclear. The lack of standardisation of different preparations and the statin-like content (monacolin K) that may elicit SAMS complicate its use. Thus, long-term RCTs are needed before the use of red yeast rice may be recommended to lower CVD risk.

Future LDL-lowering therapies for patients with SAMS

* PCSK9 inhibitors

PCSK9 is a protein that binds to the LDL-receptor to target it for degradation. Inhibiting PCSK9 with monoclonal antibodies yields large LDL-c reductions (50-60%) in several patients groups, including statin-intolerant patients. PCSK9 inhibitors show a very low rate of muscle symptoms, underscoring that it is not the LDL-c lowering per se that causes myopathy. Tolerability of these subcutaneously administered antibodies has been very good in large clinical trials. CVD outcome trials are currently ongoing.

* Cholesteryl ester transfer protein (CETP) inhibitors

CETP mediates the heteroexchange of triglycerides and cholesteryl esters between lipoproteins, and inhibiting it can markedly increase HDL-c and two CETP inhibitors (anacetrapib and evacetrapib) concomitantly lower LDL-c. No musculoskeletal side effects have been reported. Large clinical outcome trials are underway.

Overview of the pathophysiology of statin-induced myopathy

Interest in the pathophysiology of SAMS and statin-induced myopathy has primarily been directed at altered cellular energy utilisation and mitochondrial function. It seems as though statins lower mitochondrial function, attenuate energy production, and alter muscle protein degradation, which may all contribute to the development of muscle symptoms. Until recently, it was however difficult to induce myopathy with statins in preclinical models.
Contradicting results have been published on whether structural abnormalities are present in muscle tissue of patients with SAMS. Also, it has been suggested that in rare cases, statins may trigger idiopathic inflammatory myositis or immune-mediated necrotizing myopathy, thus anti-HMG-CoA-reductase antibodies may be formed.
Overall, the underlying pathophysiological mechanisms of SAMS is still largely unknown.

Genetic susceptibility to statin-associated muscle symptoms

Some variants in genes encoding drug transporters in both liver and skeletal muscle, which can increase serum statin concentration, have been linked to muscle side effects (e.g. SNP in SLCO1B1).
Also, pathogenic variants in muscle-disease-associated genes are more often seen in patients with severe myopathy, as compared with the general populations. Other candidate genes have been identified with plausible pathophysiological links to muscle metabolism, but of which no evidence for clinical relevance is available (e.g. glycine amidinotransferase [GATM]).
Genotyping of patients with SAMS in their personal or family history has been proposed, and targeted next generation sequencing of muscle disease genes may be employed to diagnose individuals at risk. But currently there is insufficient evidence to recommend genetic testing for diagnosis of SAMS.

Conclusion

The high prevalence of SAMS reported by observational studies probably negatively affects the CVD benefits of statins, since (perceived) SAMS is the main reasons for discontinuation of statin therapy. This Consensus Panel recommends that optimal therapy should combine a maximally tolerated, possibly a non-daily statin dose, together with non-statin-based lipid-lowering therapies to achieve LDL-c targets.
The documents highlights the need for further elucidation of the pathophysiology of SAMS. Observations in preclinical settings that statins may cause aberrant mitochondrial function and muscle protein degradation, should be studied in clinical setting, to hopefully offer new therapeutic options.

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